Historical Context: Cannabis • Grown for fiber and inebriation for 12,000 years
(since last Ice Age) • Emerged 36 million years ago in Central Asia • Used as medicine in China 4700 years ago
(Chinese emperor Shen-Nung, along with ginseng and ephedra)
• By 1st century CE: expanded to cover 100 medical conditions
• 1500 – 200 BCE: Egypt, Greece and India • William O'Shaughnessy: Cannabis Indica to
Western Medicine, 1838
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Presentation Notes
Humans may have cultivated cannabis for longer than any other plant. It has been grown for fiber, medicine, and inebriation for at least 12,000 years, since the end of the last Ice Age. The cannabis plant is believed to have first emerged around 36 million years ago in Central Asia, near the Altai Mountains, where Siberia, Mongolia and Kazakhstan converge. The earliest written accounts of cannabis used as medicine originate in ancient China. Legendary emperor Shen-Nung, 4700 years ago, cited cannabis as an important herbal remedy, along with ginseng and ephedra. By the first century CE, Chinese oral traditions expanded to cover over 100 medical conditions. From 1500 to 200 BCE, cannabis was used as a medicine in the Mediterranean region, in Egypt and Greece and India.
From Prohibition to Present • The U.K. banned cannabis in 1928 • By mid-1930s: banned in all 48 U.S. states.
Remained in U.S. Pharmacopeia (USP), but access impossible
• Federal government banned with the Marijuana Tax Act in 1937
• Excised from the USP in 1942 • From WW II until 1960: any research as
potential medicine discouraged • 1964: THC discovered, the “modern” scientific
era arrived
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Presentation Notes
The UK banned cannabis in 1928. By the mid 1930s, cannabis had been banned in all 48 states and though it remained listed in the US pharmacopeia (USP) as a medicine, access was virtually impossible. The federal government subsequently banned with the Marijuana Tax act of 1937. It was finally excised from USP in 1942. From World War II until the early 1960s, the US government discouraged any research into cannabis as a potential medicine. The modern scientific ear of cannabis research arrived in 1964, with the discovery the major psychoactive ingredient in cannabis: delta-9-THC.
Nearly 60% of the U.S. population now lives in states that have legalized some form of marijuana use and sales, illustrating the rising acceptance of cannabis nationwide and highlighting the industry’s immense potential for future growth. Rewind just 10 years and the map was essentially the inverse of where it is now, with pockets of light green dotting a largely white landscape. Last week, three new states joined the marijuana club: Arkansas, Florida and North Dakota, which legalized medical cannabis. Four others that already had medical marijuana laws on the books legalized recreational: California, Maine (though a recount is possible), Massachusetts and Nevada. These new markets could create $7 billion to $8 billion in additional retail revenue for the industry, according to estimates by Marijuana Business Daily. In total, 29 states plus Washington DC have legalized MMJ, while eight states plus DC have legalized recreational. After the big win in California last week, the entire West Coast has now legalized marijuana for recreational use, while 21% of the U.S. population lives in states with adult-use laws. The entirety of the Northeast and most of the northern border states have some form of legal marijuana laws on the books, leaving large swaths of the South and Midwest as the only legalization holdouts. The remaining states without legal marijuana are largely conservative – with the exception of Virginia, each of these states voted for Trump in last week’s election – but that does not necessarily preclude them from pushing something through in the future. Support for marijuana legalization does not fall strictly on party lines, as Arkansas, Florida and North Dakota all passed medical marijuana initiatives and went for Trump in the election. Momentum for marijuana legalization seems to have reached a fever pitch, and current trends suggest it will continue at a brisk pace for the forseeable future.
Medical Marijuana Laws Don't Increase Cannabis Use Among Adolescents
• Hasin, PhD et al. Columbia University data, 1991-2014, Monitoring the Future surveyed >1 million adolescents 13-18 yo
• Examined behaviors, attitudes and values • Marijuana use was higher among teenagers in
states prior to approving MM laws than states that never enacted such legislation
• Marijuana use did not increase among adolescents after the laws were passed
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Presentation Notes
Although almost half of all states have legalized the use of marijuana for medicinal purposes, a large study that included more than one million adolescents found that such legalization has not led to a rise in its recreational use among teenagers. Since 1996, 23 states and the District of Columbia have approved the use of medical marijuana. Although use of cannabis is restricted in those states, it has caused some to worry that the policy would encourage young people to use it for non-medical purposes. Deborah Hasin, PhD, a professor of epidemiology (in psychiatry) at Columbia University Medical Center in New York City, and colleagues analyzed data between 1991 and 2014 from a national study known as Monitoring the Future, which surveyed students between the ages of 13 and 18 who were in the 8th, 10th, and 12th grades. The study examines the behaviors, attitudes, and values of American secondary school and college students, as well as young adults. About 50,000 of them are polled each year. Although marijuana use was higher among teenagers in states prior to approving medical marijuana laws than states that have never enacted such legislation, use of marijuana did not increase among adolescents after the laws were passed, the researchers reported in the Lancet Psychiatry. Despite the findings, Hasin cautioned, “Because early adolescent use of marijuana can lead to many long-term harmful outcomes, identifying the factors that actually play a role in adolescent use should be a high research priority.” In a commentary to the study, Kevin Hill, MD, a psychiatrist and director of Substance Abuse Consultation Service at McLean in Belmont, Mass., wrote, “The growing body of research that includes this study suggests that medical marijuana laws do not increase adolescent use, and future decisions that states make about whether or not to enact medical marijuana laws should be at least partly guided by this evidence.” �Medical marijuana laws don't appear to lead to an increase in pot use among teens. Legalizing the medical use of cannabis has not led to a surge in the numbers of adolescents using it in the USA, according to new research that surprised its authors and will encourage those hoping for relaxation of the law elsewhere. Analyzing data from a national study called Monitoring the Future, which collects information from 50,000 pupils aged 13 to 18 in the 8th, 10th and 12th grade (years 9, 11 and 13 in Britain) every year, they found there had not been a rise even after taking into account individual, school and state-level factors that can affect marijuana use (such as age, ethnicity, public or private school and proportion of each state's population that was male or white).
Colorado has a 10 percent retail tax on marijuana and a 15 percent excise tax for larger, wholesale transactions. The state collected $70 million in taxes on pot from June 2014 to July 2015, $30 million more than amount raised from taxes on alcohol.
According to PerfectPrice, legal marijuana is cheapest in Aurora , CO but is cheaper overall in Oregon. Perfect Price tracks prices for groceries, cleaning supplies, and even marijuana in order to understand how much prices differ across areas. In this case, they surveyed in six states among the 5,000 dispensaries.��Of course the managerial economist in me wants to know why there is price variation. Possible reasons might be:�Differences in costs Differences in the level of competition among dispensaries Price discrimination against wealthier patrons Additional point-of-sale services at dispensaries catering to wealthier patrons � Interestingly, they even have data on prices from non-legal sources. The table summarizes the states but there is information at the city level too. I would be curious to know if the premium for legal weed versus street pot is related to the degree of rivalry in the two "channels."
Genetic evidence supports the argument for cannabis appearing to have split into 2 species: sativa and indica. Sativa is a fiber-type cannabis that produces more CBD and typically less than 1% THC. Indica is the drug-rich cannabis, whose THC content can reach 25% of the plants dry weight.
• Psychoactive • Anti-inflammatory • Analgesic • Neuroprotective • Spasticity • IO pressure reduction • Interacts with CB1 and
CB2
• CBD (cannabidiol): • 2nd most common in
Indica, MC by fiber (hemp) or Sativa
• Eliminates THC’s adverse effects
• Anti-inflammatory • Analgesic • In vitro: anti-cancer • Anti-convulsant • Antibiotic (MRSA) • No CB1, CB2
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Presentation Notes
More Then 700 chemical constituents are produced within the cannabis plant. Phytocannabinoids produced by the cannabis plant. THC is the most common phytocannabinoid produced by drug cannabis varieties. Certain drug varieties can produce up to 25 % of the plant's dry weight. TCH is the primary psychoactive constituent of cannabis. Besides it’s psychoactivity, THC is a potent anti-inflammatory and analgesic, neuroprotective, reduces intraocular pressure, spasticity, and muscle tension. THC interacts with both the CB1 and CB2 receptors. CBD is the most common phytocannabinoid produced by fiber cannabis (hemp) varieties and the second most common in some drug cannabis varieties. Until recently, high-CBD cannabis varieties were unavailable in the United States. No psychoactive, but some mild psychoactivity was described, though very different from THC-dominant cannabis. In cannabis medicine formulations that combine THC and CBD, such as Sativex, CBD has been shown to eliminate some of the THC’s unpleasant adverse effects, modulating its psychoactivity and reducing THC-induced sedation, anxiety and rapid heartbeat. CBD exhibits analgesic and anti-inflammatory effects across a wide range of symptoms and conditions. Cell studies have shown that CBD is also effective in vitro against lines of human brain, breast and other tumor cells, while simultaneously protecting normal cells. CBD is an effective anticonvulsant. CBD interacts with a wide range of receptors—more than THC—which may explain its broad effects. Whole CBD does not interact with CB1 and CB2, it does interact with a host of other signaling systems. CBD is even effective in inhibiting MRSA.
Cannabis is a truly a multipurpose plant. Its strong fibers have been used to make cloth and paper for thousands of years. The American declaration of independence was written on hemp paper. Cannabis seed-which is strictly speaking is a nut, is rich in polyunsaturated fats, essential fatty acids, and proteins.
Survey by International Association for Cannabinoid Medicine (IACM)
• Survey of medical conditions and the number of people treating them
• Survey of symptoms and the number of people seeking alleviation
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Presentation Notes
The results of an IACM survey on the use of cannabis as a medicine. The table of the left reveals which medical conditions are treated most frequently, and type of symptoms for which patients are most likely to seek alleviation though the use of medical cannabis.
There's a body of research showing that painkiller abuse and overdose are lower in states with medical marijuana laws. These studies have generally assumed that when medical marijuana is available, pain patients are increasingly choosing pot over powerful and deadly prescription narcotics. But that's always been just an assumption. Now a new study, released in the journal Health Affairs, validates these findings by providing clear evidence of a missing link in the causal chain running from medical marijuana to falling overdoses. Ashley and W. David Bradford, a daughter-father pair of researchers at the University of Georgia, scoured the database of all prescription drugs paid for under Medicare Part D from 2010 to 2013. They found that, in the 17 states with a medical-marijuana law in place by 2013, prescriptions for painkillers and other classes of drugs fell sharply compared with states that did not have a medical-marijuana law. The drops were quite significant: In medical-marijuana states, the average doctor prescribed 265 fewer doses of antidepressants each year, 486 fewer doses of seizure medication, 541 fewer anti-nausea doses and 562 fewer doses of anti-anxiety medication. But most strikingly, the typical physician in a medical-marijuana state prescribed 1,826 fewer doses of painkillers in a given year. In a news release, lead author Ashley Bradford wrote, "The results suggest people are really using marijuana as medicine and not just using it for recreational purposes."
Humans have used cannabis for centuries, but only in the last 50 years or so has any scientific understanding emerged as to how cannabis works within the human body. The endocannabinoid system consists of this network of endocannabinoid receptors, which are distributed throughout the body. The system is very complex system, broad in its function and found within all complex animals, from fish to humans. The two primary subtypes of cannabinoid receptor in the endocannabinoid system are CB1 and CB2. These receptors are distributed throughout the central nervous system and immune systems, and within many other tissues, including the brain, GI system, reproductive and urinary tracts, spleen, endocrine system, heart, and circulatory system.
interfere: Rimonabant for obesity (CB1 antagonist)
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Presentation Notes
The two primary subtypes of cannabinoid receptor in the endocannabinoid system are CB1 and CB2. These receptors are distributed throughout the central nervous system and immune systems, and within many other tissues, including the brain, GI system, reproductive and urinary tracts, spleen, endocrine system, heart, and circulatory system. Five endocannabinoids have been isolated. All of them are derivatives of polyunsaturated fatty acids, closely related to the omega-3 fatty acids. Not water-soluble and therefore work locally. Endocannabinoids modulate the flow of neurotransmitters. CB1 receptor is expressed throughout the brain. The list of brain functions that are affected by the endocannabinoid system is enormous: decision-making, cognition, emotions, learning, and memory, as well as regulation of bodily movement, anxiety, stress, fear, pain, body temp, appetite, sense of reinforcement or reward, motor control and much more. One brain region that does not have many CB1 receptors is the brain stem, responsible for respiration and circulation, which is a primary reason why cannabis OD is not fatal. It is activation of CB1 receptor that is responsible for the psychoactive effects of cannabis. The CB2 receptors are primarily found in blood cells, tonsils, and the spleen. CB2 receptors control the release of cytokines linked to inflammation and general immune function throughout the body. Cannabinoid-based medicines can either enhance or interfere with the endocannabinoid system’s balancing act. Rimonabant, a CB1 antagonist, was approved for sale in Europe in 2006 as an obesity treatment. It was removed from the market because of psychiatric side effects. Because the cannabinoid receptors are dispersed so widely throughout the body, activating or suppressing them for a single medical purpose can unleash a host of unwanted activity elsewhere.
• Pathogenic Molds and Bacteria: Aspergillus, Fuzarium • Too wet for too long during curing process • Aflatoxins: toxic and carcinogenic • E. coli, MRSA, anaerobic bacteria, hair, pests
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Presentation Notes
Medical cannabis needs to be clean to protect patients from dangerous exposure to pathogens, pesticides and adulterants. The best way is to insist that it has ben tested by professional laboratory, qualified to detect to detect microbiological and chemical contamination. Just because a lab can test for cannabinoid content does not always mean the lab has an equipment or skills needed to detect range of contaminants, as many labs don’t. Powdery mildew and gray mold are the most frequently reported fungal diseases of cannabis plants. Indoor cultivation sites commonly develop powdery mildew problems unless strict preventative measures are followed and adhered to. Crops cultivated outdoors in cool to moderate climates with rain during flowering season are often plagued by gray mold. Neither powdery mildew no gray mold represent any health risk to the patient—just to the plant itself. A person could smoke a bowl of gray mold, and besides its unpleasant taste suffer no ill effects. The pesticides residues are rarely toxic to mammals, but they can be used on medical cannabis plants, but they can be devastatingly toxic to honeybees or fish. Synthetic plant growth regulators (PGRs) have been used to force the plant to flower more quickly and to produce bigger and tighter buds. These chemicals are banned in the US for any plants intended for human consumption and are considered carcinogens. Always be suspicious of huge, indoor cultivated cannabis buds since they are often the result of using these illegal “pant steroids”. If an indoor cultivated bud just looks too big to be normal, the flowers may actually be toxic. Unlike powdery mildew or gray mold, the dangerous molds that can infest cannabis are difficult to detect with the naked eye. To find aspergillus, fusarium, or penicillinum molds requires lab tests. All of these dangerous molds are due to poor curing technique, not poor cultivation. They are opportunistic fungi and infest cannabis that stays too wet for too long during the curing process. Aflatoxins are not only toxic but very carcinogenic. Dangerous bacteria such as staph and E coli can also be found on cannabis. These bacteria end up on cannabis from human contact.
Synthetics and Pharmaceuticals • Marinol (dronabinol): synthetic THC analog
• First FDA-approved cannabinoid, 1985 • RX: Chemotherapy-induced nausea, HIV/AIDS cachexia • THC only adverse effects more than herbal formulation • Generic. 2.5, 5, 10 mg
• Cesamet (nabilone): synthetic THC analog • FDA-approved 1985 • RX: Chemotherapy-induced nausea and vomiting • Later onset, longer action • 1, 2 mg
• More effective than phenothiazines
• Use limited by psychoactive effects
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Presentation Notes
Marinol is the brand name for dronabinol, a synthetic THC prescription medicine which was first FDA-approved cannabinoid available in the US. Marinol is chemically identical to the THC produced by the cannabis, although it is synthesized in a lab. Marinol is typically RX for intractable nausea from chemotherapy and also treat weight loss (cachexia) in HIV?AIDS patients. Because Marinol contains only THC, at higher doses it can produce a range of adverse effects, including tachycardia, memory problems, anxiety and panic attacks. Many patients who have used both herbal cannabis and Marinol claimed that verbal cannabis produces fewer and milder her adverse affects. Marinol is now available in the United States in the generic form in 2.5, five and 10 mg dosages. Cesamet is a synthetic cannabinoids used to prevent vomiting and provide pain relief.
• Sativex (nabiximols): extracted from cannabis plants • Equal amounts of THC and CBD: modulatory “entourage
effect” (CBD as anxiolytic, antipsychotic) • Oromucosal absorption: rapid absorption, less psychoactivity,
less risk of dependence • RX: cancer pain, MS spasticity • Since 2010, approved in UK, Canada, 25 other countries • Phase III clinical trials in US, 2006- present • One spray: THC 2.7 mg + CBD 2.5 mg
• Rimonabant: synthetic cannabinoid receptor blocker • RX: obesity • 50 countries • Acute depression, SI, withdrawn in 2009
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Presentation Notes
Unlike Marinol, Topamax is of pharmaceutical cannabinoids medicine that is extracted from hold and abuse plans. The medicine is related as an RN mucosal spray that is designed to be squirted beneath the top or the inside of the cheek. It is big. Was almost equal amounts of THC in CBT, and patient’s report that does produce this fewer adverse affects than Marinol. Sativex is approved in many European countries, Canada and New Zealand and is currently undergoing phase 3 clinical trials for approval in the United States. It is used to treat spasticity due to multiple sclerosis, as well as neuropathic and cancer pain. Rimonobant was a synthetic cannabinoid pharmaceutical that was developed as a treatment for obesity. It was the first drug to be released that blocked activity of a cannabinoids receptor. At one point it was available as a diet drug in over 50 countries. Studies started to link the drug with instances of acute depression and suicidal thoughts and it was withdrawn from the market in 2009.
Cannabis Within the Body • Cannabis plant >700 chemical compounds
• Absorption of MC: • Smoked/vaporized:
• THC is detectable within few seconds • Peak blood plasma concentrations within 6-7 minutes
• Sublingual (SL), oromucosal, oral: • Absorption within 5-15 minutes • Peak within 2-7 hours • Slow, inconsistent (THC destroyed by stomach acid, first
pass metabolism) • Topical:
• Difficult, not efficient. Blending into a fatty acid • Treatment of psoriasis, osteoarthritis
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Presentation Notes
The cannabis plant produces more than 700% chemical compounds. When smoked, the THC in cannabis medicines reaches its peak blood plasma concentration within 6 to 7 minutes of ingestion. THC from smoking is actually detectable a few seconds after inhalation. Holding one’s breath slightly increase absorption. SL, oromucosal in cannabis medicines is both slow and inconsistent. It is less efficient as administration by inhalation. The inconsistency has often been cited as the reason why many oral cannabis preparations fell out of favor with both providers and patients. Maximum blood plasma levels are often reached within two hours, but in some studies human subjects have needed up to seven hours to reach those levels. Some THC is destroyed by stomach acid. Then it undergoes first-pass metabolism. Topical absorption of THC is difficult and not particularly efficient but can be accomplished by blending the THC into a fatty acid. This approach has been used to treat skin conditions including psoriasis and inflammatory ailments including osteoarthritis.
Before Using Cannabis: Contraindications • Schizophrenia, bipolar d/o, severe depression • Heart disease, hypertension, angina, arrhythmia • COPD • An immune disorder • Under 22 years old • Family history of psychotic disorders • Addictive disorders
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Presentation Notes
Cannabis users are more prone to affective disorders than their non-using samples.
https://www.drugabuse.gov/publications/marijuana/there-link-between-marijuana-use-psychiatric-disorders Whether adolescent marijuana use can contribute to developing psychosis later in adulthood appears to depend on whether a person already has a genetically based vulnerability to the disorder. The AKT1 gene governs an enzyme that affects brain signaling involving the neurotransmitter dopamine. Altered dopamine signaling is known to be involved in schizophrenia. AKT1 can take one of three forms in a specific region of the gene implicated in susceptibility to schizophrenia: T/T, C/T, and C/C. Daily users of marijuana (green bars) with the C/C variant have a seven times higher risk of developing psychosis than infrequent marijuana users or nonusers. The risk for psychosis among those with the T/T variant was unaffected by whether they used marijuana.��Source: Di Forti et al. Biol Psychiatry. 2012. The influence of adolescent marijuana use on adult psychosis is affected by genetic variables. This figure shows that variations in a gene can affect the likelihood of developing psychosis in adulthood, following exposure to cannabis in adolescence. The COMT gene governs an enzyme that breaks down dopamine, a brain chemical involved in schizophrenia. It comes in two forms: "Met" and "Val." Individuals with one or two copies of the Val variant have a higher risk of developing schizophrenic-type disorders if they used cannabis during adolescence (dark bars). Those with only the Met variant were unaffected by cannabis use.��Source: Caspi et al. Biol Psychiatry. 2005.
Adverse Effects of Medical Cannabis Most associated with THC (psychoactive). Never fatal
CBD might reduce or eliminate adverse effects
• Orthostatic hypotension lightheadedness, LOC
(Tx: keep eyes open, focus on something)
• Tachycardia: subsides within 15-20 mins (Tx: slow, steady breathing)
• If reclining upward spike of BP
• “Cottonmouth” (Tx: water, lemonade)
• Red, irritated eyes (Tx: Visine, eye drops)
• Coughing (Tx: reduce the amount inhaled, water, explore oral or SL cannabis)
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Presentation Notes
The important factor when dealing with common cannabis side effects is simply to remain calm, breathe slowly and relax. Patients who are either new to cannabis or who have overmedicated can occasionally experience a postural hypotension. This can result in lightheadedness, or LOC (especially among users of highly concentrated cannabis oils). It has been also observed that, while reclining, novice cannabis users tend to experience an upward spike in their blood pressure. Tachy: typically subsides within 15 to 20 minutes. Slow, steady breathing for a few minutes can help. Dry mouth, informally called “cottonmouth” can be addressed with water or a lemonade with added lemon peel. Dizziness and lightheadedness are less pronounced when the eyes are kept open and focused on something such as television. Red, irritated can be treated using mild eyedrops, such as Visine. Coughing caused by inhaled cannabis smoke or vapor is rarely dangerous and usually subsides quickly. It is most easily avoided by simply reducing the amount inhaled. A glass of water can also help. Brutal coughing can damage lungs. If airway irritation becomes an issue with inhaled cannabis, then oral or SL cannabis should be explored.
Long-Term Adverse Effects • Severe chronic bronchitis
• Cognitive deficits (might be reversible)
• Drug interactions
• Cannabis Hyperemesis: • vomiting and abdominal pain • relieved by hot bath or shower • resolved completely upon cessation
• Heart attack, stroke
• OD: 3-8 hours: • hallucinations, panic, nausea, tachycardia, paranoia • never fatal • call 911 if victim is a child
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Presentation Notes
There can be long-term adverse effects from using cannabis, which is why responsible physicians recommend a defined course of treatment for their patients. Heavy, long term smokers can develop severe and chronic bronchitis. A range of cognitive deficits has been noted in long-term cannabis users. Some evidence indicates that some of these deficits can be reversible. When taken orally, the active ingredients in cannabis medicines can affect of metabolism of other medications (decrease the metabolism of Diltiazem, fluconazole and increase the metabolism of phenobarb, phenytoin). Cannabis hyperemesis is characterized by vomiting and abdominal pain associated with the use of cannabis. A recent study at Mayo looked at 98 reports. In many the symptoms seemed to be relieved by taking either a hot bath or shower. The syndrome is also reported to resolve itself completely upon cessation of cannabis use.
Early-Onset, Regular Cannabis Use Is Linked to IQ Decline
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Presentation Notes
https://www.drugabuse.gov/news-events/nida-notes/2013/08/early-onset-regular-cannabis-use-linked-to-iq-decline The study participants were 1,037 people who were born in 1972 and 1973 in Dunedin, New Zealand, and enrolled as infants in the longitudinal Dunedin Multidisciplinary Health and Development Study. Their families represented the range of socioeconomic statuses in that region. Dr. Meier and her team tested each participant’s IQ four times up to age 13; asked about past-year cannabis use at ages 18, 21, 26, 32, and 38; and assessed IQ again at age 38. The researchers used the Wechsler Intelligence Scale for Children-Revised (WISC-R) and the Wechsler Adult Intelligence Scale-IV (WAIS-IV) to assess IQ in childhood and adulthood, respectively. The team averaged each participant’s four childhood IQ scores and compared that number with his or her score at age 38.
Cancer Glaucoma HIV/AIDS Cachexia (wasting syndrome) Pain Nausea Seizures Muscle spasms Multiple sclerosis PTSD Hepatitis C (AR) ALS or Lou Gehrig’s Disease Tourette’s Syndrome Crohn’s disease Severe arthritis Fibromyalgia Alzheimer’s disease A chronic or debilitating disease that produces: Cachexia or wasting syndrome Peripheral neuropathy Intractable pain Severe nausea Seizures Migraines Any other chronic or persistent medical symptom that substantially limits the ability of the person to conduct one or more major life activities (as defined by the Americans with Disabilities Act of 1990) or, if not alleviated, may cause serious harm to the patient’s safety or physical or mental health Parkinson’s disease Damage to the nervous tissue of the spinal cord with objective neurological indication of intractable spasticity Epilepsy Lou Gehrig’s disease (amyotrophic lateral sclerosis, or ALS) Any condition diagnosed as “debilitating” by a licensed physician Seizure disorders related to diagnosis of epilepsy or trauma-related head injuries Mitochondrial disease (GA) Sickle cell disease (GA) Arnold-Chiari malformation and syringomyelia (IL) Causalgia Chronic inflammatory demyelinating polyneuropathy CRPS (Complex Regional Pain Syndrome Type I) (IL) CRPS (Complex Regional Pain Syndrome Type II) (IL) Dystonia Fibrous dysplasia (IL) Hydrocephalus (IL) Interstitial cystitis (IL) Lupus (IL) Muscular dystrophy (IL) Myasthenia gravis (IL) Myoclonus (IL) Nail-patella syndrome (IL) Neurofibromatosis (IL) Post-concussion syndrome (IL) Residual limb pain (IL) Rheumatoid arthritis (RA) (IL) Sjogren’s syndrome (IL) Spinal cord disease (including but not limited to arachnoiditis, Tarlov cysts, hydromyelia & syringomelia) (IL) Spinal cord injury (IL) Spinocerebellar ataxia (SCA) (IL) Traumatic brain injury (TBI) (IL) Symptoms related to cancer (LA) Spastic quadriplegia (IL) Terminal illness Hepatitis C infection currently receiving antiviral treatment Inflammatory autoimmune-mediated arthritis Hospice patients Huntington’s disease (NY, PA) Spinal stenosis (ND) Lennox-Gastaut syndrome (<18 yo, OK) Dravet syndrome (<18 yo, OK) Severe myoclonic epilepsy of infancy ((<18 yo, OK) Sickle cell anemia (PA) Autism (PA) Glaucoma: The pressure in the eye caused by this condition can be reduced by smoking cannabis but Professor Keith Green, Director of ophthalmic Research at the Medical College of Georgia said some 6 ‘joints’ a day would be required, rendering the patient effectively ‘stoned’ and incapable of useful activities.�MultipleSclerosis: Dr Donald Silberg. Chief of Neurology, Pennsylvania school of Medicine said, “I have not found any legitimate or scientific works which show that marijuana is medically effective in treating Multiple Sclerosis or spasticily. The use of marijuana especially for long-term treatment would be worse than the illness itself’.
AZ AK CT IL AR PA OH OH DC AR AZ AR NH FL DE DE DE OH CA IL MI OH CT ME MT NM IL MI NV MN MA NH OH PA NH OR RI NV ND RI NM MI OH OH OR ME NV ND VT WA
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Arizona, Arkansas, Delaware, Illinois, Maine, Michigan, New Hampshire, North Dakota, Oregon, Ohio and Rhode Island. PTSD: Arizona, Connecticut, Delaware, Maine, New Mexico, and Pennsylvania
Cannabis and Pregnancy • Risk of infertility (ovulatory abnormalities)
• CC: nausea, depression
• Negative effects on prenatal, neonatal and child development (2014 Swedish animal study): THC interferes with fetal brain development
• Study of 600 British women who smoked Cannabis: NO: risk of infant mortality; reduced birth weight
• Ottawa Prenatal prospective study (OPPS), Maternal health practices study and child development study (MHPCD): NO: higher rates of miscarriage, premature birth, childbirth complications. YES: For 3-4 year olds: impaired verbal and memory domains, short-term memory, verbal reasoning, attention-deficit, executive functioning (smokers in 1-2 trimester)
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Presentation Notes
Women using cannabis have ab elevated risk of infertility due to ovulatory abnormalities. Some women choose to continue to use cannabis during pregnancy to reduce nausea from morning sickness and depression. A study of 600 British women who smoked cannabis was examined to assess the impact of their pregnancies. Cannabis use during pregnancy was not associated with increased risk of infant mortality. However, frequent use of cannabis throughout the pregnancy maybe at associated with reduced birth weight.
Medical Cannabis in the Workplace • Many corporate zero-tolerance drug policies
• No detectable amount of illegal drugs • No accommodations, users may lose
employment • AZ, CT, DE, ME, RI: laws protect from hiring
discrimination or disciplining if UDAS is (+) for cannabis
• No protection if the patient is “impaired”
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Presentation Notes
Even though the patients using medical cannabis may not use it at work or come to work under its influence, many corporate zero tolerance drug policies makes no accommodation whatsoever for this patients. Zero-tolerance workplace rules prohibit any detectable in amount of illegal drugs in an applicant or employee’s blood system and this recognition is typically extended to medical cannabis. Many state medical cannabis statutes failed to provide accommodation for this issue and because THC metabolites can be detected long after a user is impaired or influenced by the use of cannabis, users may still lose their employment if cannabis use is detected through a mandatory drop testing. Medical cannabis laws in Arizona, Connecticut, Delaware, Maine and Rhode Island specifically protect medical cannabis patient’s from hiring discrimination. Arizona and Delaware prohibit businesses from refusing to hire applicants or disciplining employees on the basis of drug tests that uncover cannabis components or metabolites. However, there is no protection and these states if the patient is impaired from their use of medical cannabis. There are no reliable guidelines for defining impairment based on blood levels of THC or other cannabis constituent or metabolites.
Driving and Cannabis • Dose-dependent impairment of automatic skills, but
generally mild, cautious “insightful” style, compensate • max in 20-40 minutes after smoking • vanishes in 2.5 hours
• Cannabis (automatic) + alcohol (complex) = more severe impairment even at low doses of both
• Decreased driving speed, time and distance perception, coordination, decision making, concentration
• Blood concentration 13 ug/L weaving similar
to EtOH of 0.08 (5 ug/L is a limit in CO, WA)
• If drunk – you run the RED lights;
if stoned – you stop at the GREEN lights
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Presentation Notes
It has been shown that combining alcohol and cannabis more severely impairs driving abilities. Impairment of driving ability by cannabis seems dependent on dose. In cognitive tests related to driving performance, cannabis has been shown to impair performance, with the level of impairment dependent on the dose. Few tests have been shown to only slightly impair actual driving performance. Maximal impairment is found 20 to 40 minutes after smoking, but the impairment has vanished 2.5 hours later. Cannabis appears to most negatively influence highly automative driving tasks, such as staying within a lane, rather than complex driving tasks, such as merging into traffic. Dose-dependent impairment of automatic skills, but generally mild max in 20-40 minutes after smoking vanishes in 2.5 hours Cannabis + alcohol = more severe impairment Highly automative skills (staying within a lane) impaired Complex driving tasks are not impaired Decreased driving speed, time and distance perception, coordination, decision making, concentration impaired More cautious “insightful” style, compensate Blood concentration 13 ug/L weaving similar to EtOH of 0.08 (5 ug/L is a limit in CO and WA)
Historically, marijuana was not seen as a drug of dependence in the same way as heroin or alcohol, but marijuana dependence is now well recognized in the scientific community. In the United States, 49% of people have used cannabis. Among individuals who have ever used cannabis, 9% develop dependence. Cannabis withdrawal sx include insomnia, irritability, anxiety, mild depression, moodiness, GI sx and nausea. Treatment approach includes stress management techniques and pharmacological interventions for alleviating loss of appetite and insomnia. Symptoms rarely persist more than 14 days.
“Legal yet illegal. Is there a sane solution?” • Schedule I status
• To do clinical research, approval of: • DEA for issuance of a license • FDA for approval of a protocol • NIDA to use botanical cannabis
• Little financial incentive to launch multimillion-dollar studies on a ubiquitous plant
• States with MC legalized: in defiance with federal constraints. Federal statutes trumps the state statutes
• MDs Rx MC violate federal law: risk of losing DEA license, face criminal prosecution; no clear guidance for practitioners and patients
• Rescheduling to Sch II: research to develop meds, improve efficacy and minimize side effects
Presenter
Presentation Notes
Schedule I drugs, substances, or chemicals are defined as drugs with no currently accepted medical use and a high potential for abuse. Schedule I drugs are the most dangerous drugs of all the drug schedules with potentially severe psychological or physical dependence. Some examples of Schedule I drugs are: heroin, lysergic acid diethylamide (LSD), marijuana (cannabis), 3,4-methylenedioxymethamphetamine (ecstasy), methaqualone, and peyote. To do clinical research using cannabis, an investigator must gain the approval of two federal agencies: the DEA for issuance of a license and the FDA for approval of a protocol authorizing use as an investigational new drug. The researcher than would need to petition a third agency, NIDA, for the right to use the only federally acceptable research-grade cannabis, a strain from 1970s grown to order on a farm under the auspices of the university of Mississippi. Couple all of this with the reality that there is little financial incentive for pharmaceutical companies to launch multimillion-dollar studies on a ubiquitous plant. The states that have legalized mc have essentially gone in defiance of federal constraints. Both federal and state governments have implemented laws to regulate Marijuana use. In the US when federal and state laws are in disagreement, the federal statute trumps the state statute. With the federal state government having declared cannabis illegal, practitioners who prescribe MC violate federal law and run the risk of losing their DEA license or facing criminal prosecution. With states proceeding as if their laws are legitimate and the federal government erratically enforcing its own statues outlawing cannabis use for any purpose, patients and health care providers are left with no clear guidance. In june of 2011 DEA refused to reschedule cannabis. Schedule II status would facilitate development of additional cannabinoid derived medications. Research could go forward with the goal of deriving cannabis-based pharmaceuticals.
Pickup any alternative newspaper in San Francisco, Denver, Los Angeles, and you will see advertisements for G13 Kush, blue lightning, Charlie Sheen kush, Obama cookies and so on. There 100 s of medical cannabis varieties being marketed by store front dispensaries and delivery services. The average person looks at this and thinks “where do they get these ridiculous names?”. The answer is, they are made up. If the names are just made up what are the chemically distinct varieties of cannabis that these companies claim to be selling? Nobody really knows, including the folks selling them. This ignorance is usually not malicious, and cultivators do try to make informed guesses as to identities of the cannabis varieties they provide. But there are not many standards or certification procedures in California or Colorado, although that is hopefully changing. In 2013 legislation was introduced in Connecticut two regulate medical cannabis, and its requires products to have brand names. Chemical fingerprinting determines the normal range of THC and CBD produced. Each variety of cannabis contains genes that determine its specific chemical composition. Production of each essential oil and cannabinoid by the plant is controlled by expression of genes. While it is clear that medicinal or psychoactive effect are influenced by the ratio of cannabinoids, the result of the interaction is extremely complex and still not completely understood. Principal component analysis of cannabis will be able to predict the effects of cannabis variety more accurately, by mapping its chemistry
• Dosage: For sedation: THC 5-10 mg PO (edibles); • High doses agitation, disorientation. • For inflammation: CBD 160 mg (600 mg)
•Future: slow the buildup of beta-amyloid plaques and tangles. MOA: THC lowers amyloid-beta levels and enhancing mitochondrial function (Cao, et al., 2014) (Currais, et al., 2016 (Eubanks, et al., 2006).
• CBD modulates microglial function, controls neuroinflammation (Martin-Moreno, et al., 2011). CBD: neuroprotective, anti-oxidative, anti-inflammatory and anti-apoptotic effects (Iuvone, et al., 2004). CBD promotes regeneration of brain cells (Cheng, et al.,
2014). CBD increases glucose uptake (Köfalvi, et al., 2016).
Presenter
Presentation Notes
THC has been shown to be effective at lowering amyloid-beta levels and enhancing mitochondrial function, therefore causing the researchers to conclude “that THC could be a potential therapeutic treatment option for Alzheimer’s through multiple functions and pathways” (Cao, et al., 2014) (Currais, et al., 2016). An earlier study also found THC to be effective at preventing amyloid beta aggregation, suggesting it could impact the progression of the disease (Eubanks, et al., 2006). The brains of Alzheimer’s patients experience an over activation of microglia (cells that form myelin), which contributes to the excessive tau buildup and therefore tangles. However, CBD has been shown to modulate microglial function and control neuroinflammation (Martin-Moreno, et al., 2011). In addition, CBD has been shown to improve the survival rate of cells through a combination of neuroprotective, anti-oxidative, anti-inflammatory and anti-apoptotic effects against the toxicity caused by beta-amyloid, therefore showing potential as a therapeutic option for Alzheimer’s (Iuvone, et al., 2004). One study that found CBD’s neuroprotective effects and its ability to promote the regeneration of brain cells was effective for reversing the cognitive deficits caused by Alzheimer’s (Cheng, et al., 2014).� A lack of glucose uptake has been linked to a worsening of brain diseases like Alzheimer’s disease, and findings in a 2016 animal trial suggest that cannabis could promote an increased glucose uptake in the brain, thereby potentially being beneficial for treating Alzheimer’s disease (Köfalvi, et al., 2016).� Cannabinoids provide a multi-faceted approach in the treatment of Alzheimer’s. In addition to reducing amyloid-beta levels, modulating microglial function and increasing glucose uptake, they protect brain cells from the deleterious effects of amyloid-beta, reduce inflammation, and support the brain’s repair process by enhancing neurogenesis (birth of new cells) (Campbell & Gowran, 2007).
ADHD (AR) • Can encourage “hyper focus” 90 minutes. Less
successful than Rx meds. Reduce “jitters” of stimulants.
• ADHD: 1. Dysfunction of DA system. DA receptors interact
with endocannabinoid system, CB1 in limbic system (amygdala, hippocampus)
2. Endocannabinoid (EC) deficiency -> restlessness, impulsivity, and inattention. Cannabis -> activates EC system -> DA release-> slows the speed of neural impulses
• Dosage: micro-doses THC 2.5 mg
• Methods: oral—sedating, SL better, smoking--bad
• No effect on attention without ADHD Dx
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Presentation Notes
Case report Cannabis improves symptoms of ADHD Peter Strohbeck-Kuehner, Gisela Skopp, Rainer Mattern As seemingly unbelievable as it sounds, other doctors and marijuana advocates have affirmed this finding. Dr. Claudia Jensen, who frequently prescribes pot for attention disorders, says that the natural drug is better than Adderall or Ritalin. One of Jensen's patients with ADHD who had previously had no luck with pills—a 15-year-old boy—was finally able to attend school regularly after beginning a regimen of cannabis candy, according to Fox News. Dr. David Bearman, who works with medical marijuana patients, has said that weed can even improve grades in patients with ADHD. Dr. Bearman frequently quotes one of his patients who told him, "I got my PhD because of smoking marijuana." Under pot's influence, I could barely type the above sentences.Under pot's influence I, however, could barely type the above sentences, so I called Dr. Bearman to talk to him about how, exactly, weed helps ADHD patients concentrate. It turns out that cannabis affects patients with ADHD differently than patients without attention disorders. "Cannabis works by stimulating the endocannabinoid system," reminds Dr. Bearman. "The reason that cannabis has an effect on us is that we have receptors that can either be stimulated or blocked by the 21 cannabinoids in cannabis." When these receptors are stimulated it causes a release of dopamine, which decreasing overstimulation in the brain. Patients with ADHD, says Dr. Bearman, have an endocannabinoid deficiency, causing restlessness, impulsivity, and inattention. "Those with endocannabinoid deficiencies are more likely to be anxious and have attention-deficit disorder," explains Dr. Bearman. Endocannabinoid deficiency and its link to certain conditions was first identified by Ethan Russo, a former medical advisor at GW Pharmarcuticals. "Cannabis slows down the speed of neural transmission. So the fact that neural impulses are slower allows the cerebral cortex to focus and concentrate on one or two of those impulses, rather than being overwhelmed by a large amount of neural impulses coming into the brain," says Dr. Bearman. Adderall and Ritalin, two drugs commonly prescribed for ADHD, also regulate dopamine levels. "The difference is in the side-effect profiles," says Dr. Bearman. "Those drugs cause jitteriness, anxiety, and decreased appetite. With cannabis, the side-effects can be decreased anxiety, increased appetite, and assistance with sleep." A new study, according to Metro, reported that 22 of the 30 participants with ADHD opted to "discontinue their prescribed pharmaceutical drugs and continue solely with the medicinal cannabis." Cannabis isn't as effective in upping attention levels for people without ADHD.But while pharmaceutical pills are frequently used by those who just want an edge on the SAT, or in the office, cannabis isn't as effective in upping attention levels for people without ADHD, says Dr. Bearman. Extremely stoned, and on my third Fruit Roll-Up, my highly scientific experiment came to the same conclusion. "I have some people [without attention-disorders] that say [cannabis helps them focus], but in my experience patients with ADHD benefit the most. If your endocannabinoid system is working perfectly OK, in terms of controlling the speed of neural transmission because you have enough cannabinoids, then adding on the extra cannabinoids isn't necessary. "They will still have an effect, but they're not going to effect your attention issues, because you don't have a problem with attention," says Dr. Bearman. Fair enough.
1. ASD: 5 times the number of CB2 receptors • CB1 and CB2 receptor abnormalities to social
and emotional disturbances. Poor functioning CB2 response to increase CB2 receptor count
2. NL3 mutations inhibit secretion and signaling of endocannabinoids increase in pro-inflammatory cytokines levels in ASD CB2 upregulation in response to inflammatory stimuli as neuroprotection
• Methods: oral, vap for teens, THC+CBD
Presenter
Presentation Notes
The importance of the discovery of the role that the endocannabinoid system (ECS) plays in human health and disease cannot be understated. Cannabinoid receptors are the most highly expressed of any G-protein coupled receptor (GPCR) in the body. They’re the only ones to play a direct role in virtually every aspect of the human body (CNS and immune systems, throughout the periphery, presynaptic, and postsynaptic).[1] It’s no wonder that anecdotal reports of cannabis treatments indicate effectiveness in such a wide array of conditions. The growing body of scientific research surrounding the endocannabinoid system continues to lead to the further understanding of the physiological basis in a growing number of conditions.[45] One condition with both supportive anecdotal and preclinical scientific evidence is for patients on the severe end of the autism spectrum (ASD). In a short series of articles we’ll attempt to shed light on the role that the endocannabinoid system plays in the progression of autism, the potential role of phytocannabinoids in treatment, and what that might mean in a practical sense. NL3 Mutations Inhibit Tonic Endocannabinoid Secretions Neuroligins are part of a family of neuronal cell surface proteins that “connect presynaptic and postsynaptic neurons at synapses, mediate signaling across the synapse, and shape the properties of neural networks by specifying synaptic functions”. Alterations in genes encoding neuroligins are associated with autism and other cognitive diseases.[56] Mutations in neuroligin-3 (NL3), a member of the family of neuroligins, are associated with ASD.[17] NL3 is required for tonic secretion of endocannabinoids (AEA, 2-AG).[17] NL3 mutations have been shown to inhibit tonic endocannabinoid secretion.[17] This dysregulation in endocannabinoid signaling may contribute to the pathophysiology of autism.[17, 50, 53] These findings have in part prompted researchers to apply to conduct research with nonhuman primates in order to further elucidate this association.[39] Targeting Endocannabinoid System to Treat FXS Fragile X syndrome (FXS) is the most commonly known genetic cause of autism.[30] FXS is associated with a loss of the fragile X mental retardation protein (FMRP) which regulates signal transduction in the brain.[30] This FMRP deficiency is believed to “increase neuronal excitability which is mediated by endocannabinoids”.[59] FXS is also associated with “neuropsychiatric problems such as hyperactivity, attention disorders, and seizures.”[19] The endocannabinoid system is key to modulating functions that are involved with regulating all of these disorders including “synaptic plasticity, cognitive performance, anxiety, nociception and seizure susceptibility.”[19] The endocannabinoid system is specifically implicated in just about all aspects of FXS including “behavioral, synaptic and molecular manifestations.”[19] Preclinical research implicates CB1 and CB2 as pharmacological targets with the potential to reduce cognitive deficits and anxiety in FXS models in rodents.[19, 59] Increased Expression of CB2 Receptors Associated with ASD Though it wasn’t long ago that the role that CB2 receptors played in the human brain was believed to be negligible, additional research has implicated it as having a much more substantial role than previously understood. “Given that CB2 is up-regulated, and that it’s believed to play a neuroprotective role, CB2 is being investigated as a potential target for treatment of ASD.[53]” One example is that CB2 is believed to play a neuroprotective role in response to a variety of inflammatory stimuli, this has implications in a number of neuropsychiatric conditions including ASD.[4, 16, 53] In ASD, as well as a number of conditions, the expression level of CB2 receptors increases in response to the inflammatory nature of the condition.[16, 53] Given that CB2 is up-regulated, and that it’s believed to play a neuroprotective role, CB2 is being investigated as a potential target for treatment of ASD.[53] Elevated Cytokine Levels Associated with ASD In part one of this series the preclinical scientific evidence illustrating the involvement of the endocannabinoid system (ECS) in the physiological progression of Autism Spectrum Disorder (ASD) was provided. Here we’ll highlight some of the pharmacological characteristics that phytocannabinoids share with endocannabinoids, the use of phytocannabinoids in the treatment of symptoms and diseases associated with ASD, and why having access to a variety of cannabis chemotypes will always be preferable to a select cannabinoid and/or ratio. The anecdotal reports of successful cannabinoid therapies seem to be supported by the fact that phytocannabinoids from cannabis, and other natural sources, display similar pharmacological characteristics to that of endocannabinoids that are dysregulated in ASD.[31] The potential therapeutic value of supplementing the endocannabinoid system with phytocannabinoids has been suggested in the treatment of a number of diseases with suspected underlying endocannabinoid deficiencies.[34] Documentation of the safety and clinical efficacy of phytocannabinoids in a variety of treatments continues to grow.[16] In regards to the treatment of ASD, some similar characteristics are worth highlighting, including: Promotion of Neurogenesis[19, 2, 5] Neuroprotection[15, 23, 35] Powerful Antioxidants[3, 31, 15] Neuromodulation[8, 23, 31, 43] Anti-inflammatory[31, 18] Based on preclinical research ECS deficiencies appear to be associated with ASD, and it’s implicated as a potential target for treatment. Phytocannabinoids target the ECS and display similar pharmacological characteristics to endocannabinoids that are dysregulated. It’s been suggested that therapies for conditions with corresponding ECS deficiencies may include supplementation with phytocannabinoids. This seems to potentially support the anecdotal reports of successful cannabinoid therapies in ASD. Treating Symptoms Associated with ASD There is a considerable body of supportive preclinical data in regards to targeting the ECS with phytocannabinoids in the treatment of a number of symptoms and diseases associated with ASD. For sake of brevity some of these will be highlighted and cited: G.I. Disorders[4, 10, 42] Repetitive Behaviors[6, 9, 14] Seizures[20, 32, 40] Sleep Dysfunction[28, 41] Self Injurious Behavior and Tantrums[27, 29, 30] Tuberous Sclerosis[21, 38, 44] Cerebral Ischemia[37, 7, 26, 12] Depression/Anxiety[17, 1, 36] Cachexia[11, 24] Again, anecdotal reports of success appear to be supported by an abundance of preclinical research that indicates a potential role for phytocannabinoids in the treatment of symptoms and diseases associated with ASD. Botanical Extracts > Dronabinol Due to the relatively common off-label use of Dronabinol (a man-made/synthetic form of THC), for ASD therapy, it seems relevant to point out the substantial data, including clinical studies, suggesting that the combined administration of CBD along with THC (and possibly other cannabinoids/terpenes present in cannabis) exhibit additive and synergistic effects. This is known as the entourage effect and results in greater clinical efficacies when compared to either cannabinoid alone.[25, 18, 34] The second most prominent cannabinoid in cannabis is cannabidiol (CBD).[13] CBD has been shown to inhibit intoxication, sedation, and tachycardia associated with delta-9-tetrahydrocannabinol (THC).[34] It’s been shown to increase the clinical efficacy of THC, while adding therapeutic value in its own right.[34] A large portion of the research conducted thus far with ASD and cannabinoids has been with Dronabinol (a synthetic form of THC) alone. Dronabinol has indicated potential for treatment in a single adolescent case study of autism.[22] Does that mean THC along with CBD might offer increased clinical efficacy similar to the way they have been demonstrated to with other conditions?[34] Based on the results of previous research and anecdotal reports this might be the case. The added benefit of additional cannabinoids (and the added benefit of specifically tailoring ratios) is an important component that sets botanical extracts from cannabis apart from THC or CBD alone. This is why having access to a variety of cannabis chemotypes will always have more potential for therapeutic value than a select cannabinoid, ratio, or cannabis chemotype. Discussion Based on their ability to target the ECS, and their shared characteristics with dysfunctional endocannabinoid levels, preclinical evidence supports the potential therapeutic value of phytocannabinoids in ASD therapy. Highlighting individual pharmacological characteristics of CBD, THC, and other phytocannabinoids is beyond the scope of this paper. However, based on the ECS deficiencies associated with ASD, and the ability of phytocannabinoids to target and modulate aspects of the deficiencies, anecdotal reports seem to be supported by the best available scientific data. It appears that phytocannabinoids have the potential for therapeutic value in some severe cases of ASD. This brings us to the topic of the final installment to this ASD series, the practical use of botanical extracts and when it might be appropriate to explore potential cannabis-based therapies for ASD symptom treatment. “Cytokines are small secreted proteins released by cells that have a specific effect on the interactions and communications between cells… Pro-inflammatory cytokines are involved in the up-regulation of inflammatory reactions.”[60] Elevated pro-inflammatory cytokine levels are associated with ASD.[44] Whether this is due in part as a result of NL3 mutations inhibiting tonic secretion of endocannabinoids remains uncertain. However, endocannabinoids (AEA, 2-AG) have been shown to play key roles inhibiting cytokines via CB2.[12, 47] The majority of cannabinoids have been demonstrated to decrease cytokine production via CB1/CB2 dependent and independent mechanisms.[25, 27, 29, 36] Clinically Diagnosing ASD via the ECS A team of researchers recently discovered and patented a process that claims that it’s possible to clinically diagnose ASD, and susceptibility to it, via observation of the degree of modulation that acetaminophen has on endocannabinoid levels. However, based on a series of deductions made within their published literature, it appears that additional research is required. Other Relevant ECS/ASD Implications The number of functions that ECS regulate is extensive and beyond the scope of this paper.[45, 48] However, a few potentially relevant aspects to ASD will be listed: “CB1 variations modulate the striatal function that underlies the perception of signals of social reward, such as happy faces. This suggests that CB1 is a key element in the molecular architecture of perception of certain basic emotions. This may have implications for understanding neurodevelopmental conditions marked by atypical eye contact and facial emotion processing, such as ASC.”[13] “Endocannabinoids are key modulators of synaptic function.”[11] Tonic secretions of endocannabinoids regulate GI functions (including metabolism).[15, 37] Endocannabinoids regulate stress responses, in part via the modulation of the 5-HT system.[23] Additional targets of endocannabinoids (and exogenous cannabinoids), PPARα, PPARγ, and GPR55 expression levels have shown reductions in a valproic acid model of autism in rats.[33] Conclusion Based on the preclinical research the endocannabinoid system appears to be directly impacted by, as well as a potential target for treatment of, physiological manifestations of genetic factors associated with ASD including NL3 mutations and FXS. NL3 mutations inhibit tonic secretion of endocannabinoids and disrupt their signaling. This possibly contributes to the identified increase in pro-inflammatory cytokines levels in ASD. CB2 is upregulated in the brain in response to inflammatory stimuli as part of a neuroprotective role, and is suggested as a target for treatment. There appears to be a preponderance of evidence that the ECS is involved in the progression of ASD. In our previous installment, we provided a brief overview of the preclinical research implicating the role that the endocannabinoid system (ECS) plays in the progression of autism spectrum disorder (ASD), preclinical research supporting targeting the ECS to treat ASD, and provided a number of preclinical studies indicating the potential value of phytocannabinoids in treating symptoms and diseases associated with ASD. Here we’ll examine the shortcomings of current research, explore possible adverse effects of cannabinoid treatments, discuss the types of autism that may currently warrant cannabinoid treatments, and illustrate how a family might systematically approach a cannabinoid treatment for ASD. Cannabis Therapy Uncertainties While the preclinical research appears promising, it’s important to note that preclinical research doesn’t always translate into clinical efficacy; although, anecdotal reports of success do lend themselves to the idea of promise. Additionally, treatments are made more complex by the wide spectrum of ASD and the genetic conditions associated with it.[1, 2] Specific cannabinoids and ratios of cannabinoids (as well as terpenes and flavonoids) that offer the most therapeutic value may vary on an individual case by case basis. Preclinical research does not yet provide clear cut answers in regards to how to target the endocannabinoid system to treat ASD. CB1 and CB2 blockade decreased cognitive deficits and anxiety, respectively, in some FXS models.[2, 10] Other models indicate the beneficial aspect of combating neuroinflammation via CB2 activation.[9, 5] Many of the symptoms associated with ASD are treated via CB1 activation as cited in the previous article of this installment. The NL3 models indicate a benefit from increasing endocannabinoid levels.[1] NL3 mutations and FXS both have a wide spectrum of dysfunction, the degree of which is different in every patient. [1, 2] Therefore, each patient may display varying ECS dysfunctions and, in turn, require varying ratios of cannabinoids for therapy. This is why it may be important to have access to a selection of cannabis varieties with known ratios of cannabinoids present (primarily CBD:THC). Possible Adverse Effects When considering a cannabis treatment for an underage patient and/or a developing brain there may be adverse effects from cannabis treatments that should be considered. Acute and chronic administration of delta-9-tetrahydrocannabinol (THC) has been demonstrated to cause mild cognitive deficits related to memory and learning via CB1 activation in healthy brains in some mouse models.[8] “According to anecdotal reports, an increased ratio of THC is required to increase the efficacy of some treatments. The range seems to vary significantly from 24:1 to 1:1 (CBD:THC) with fewer outlying cases reporting success from higher THC ratios.” While this characteristic is not to be downplayed or overlooked, it should be pointed out that low doses of THC also activate preconditioning and post-conditioning mechanisms that protect the brain from more severe insults.[8] This may be relevant because autistic brains are more vulnerable to environmental toxicity, oxidative stress, neuroinflammation, and neuronal insults.[4] That being said the possibility of adverse effects from cannabinoid therapies should be considered in pediatric patients. This is due to the concern of the unknown impact that cannabis treatments, particularly THC, has on a developing brain. An argument could be made that botanical extracts with cannabidiol (CBD) present might offer safer options for patients, with greater clinical efficacy, when compared to THC alone.[7] This is partly why having access to CBD is important to ASD therapies, but it offers much more therapeutically than simply increasing the safety and efficacy of THC.[3] When is Cannabis Therapy the Right Choice? While these articles cannot be taken as professional medical advice, the authors agree that based on the available data, generally speaking cannabis based therapies might only be warranted in the most severe cases of ASD, and only as a last-line therapy under the guidance of a qualified physician. If a patient has a form of ASD that is truly severe, is unresponsive to available treatments, and the patient’s condition will deteriorate if no therapy is implemented, we believe that their family and physician should be legally permitted to make the decision as to whether botanical extracts from cannabis may be a viable option for treatment. Additionally, having access to both CBD and THC is optimal for the success of a cannabis therapy for ASD. A Practical Approach to Cannabis Therapy How can combinations of cannabinoids be put into practical use by individual families? For our purposes let’s review the anecdotal reports of cannabinoid based treatments currently being utilized in ASD as well as pediatric epilepsy. This might be a good comparison due to the range and complexity of both conditions and similarities in genetic dysfunctions. CBD-only extracts continue to prove effectiveness in treating many types of epilepsy, but not all.[6] According to anecdotal reports, an increased ratio of THC is required to increase the efficacy of some treatments. The range seems to vary significantly from 24:1 to 1:1 (CBD:THC) with fewer outlying cases reporting success from higher THC ratios. Due to the range of ASD it seems possible that, similar to cannabinoid-based epilepsy treatments, varying ratios of cannabinoids (specifically CBD:THC) will prove to have a greater efficacy overall when compared to individual cannabinoid based treatments. The greater the ability to adjust the cannabinoid ratios the more optimal the conditions are to achieve therapeutic value. Though, generally speaking, they’re predominantly extracts that are high in CBD content. “In ASD treatments, a first line of action to approaching a cannabis therapy might be to try a particularly high CBD ratio.” In ASD treatments, a first line of action to approaching a cannabis therapy might be to try a particularly high CBD ratio. A high CBD containing botanical extract would be taken orally. The quantity of this botanical extract would slowly be increased incrementally based on weight until a desired effect, no effect, or an adverse effect is identified. If CBD alone is not sufficient to achieve a desired effect, a strain with higher content of THC is used, or an additional botanical extract that has a high THC content is added to a CBD extract in order to achieve the desired CBD:THC ratio. Again, this is incrementally increased based on weight until a desired effect, no effect, or an adverse effect is identified. More information on regiments can be found on Facebook in groups focusing on cannabis based pediatric therapies. The ability to procure various ratios of cannabinoids in order to specifically tailor therapies may prove paramount to the effectiveness of treatments. Generally when parents find a strain or ratio that works well for them they try and stick with it. There are numerous cannabis varieties with varying ratios of cannabinoids in the majority of medical cannabis States. Seeking out plants that have been used in other ASD or epilepsy treatments might be a good first step. Moving Forward As future research is published we may see advances in the treatment of ASD by targeting the ECS. Until then we remain largely in the dark with possible glimmers of hope on the horizon. The mere possibility of combating ASD is enough for some families to explore cannabis as a treatment option, generally families unable to wait for possible future advances. The question of when it becomes acceptable to provide a cannabis based treatment to a pediatric patient is complicated and loaded with moral and legal implications. The wide spectrum of ASD, the uncertainties in regards to targeting the endocannabinoid system for this treatment, and the possible adverse effects of THC therapy in pediatrics, all lend to the complexity of the issue. In States with approved medical cannabis programs, it’s imperative that ASD be added to their lists of qualified medical conditions for approval of cannabis licenses. Parents and physicians should have the right and legal protection to explore cannabis as a treatment option, especially as a last-line therapy in ASD. https://www.medicaljane.com/2015/06/17/part-three-practical-approach-to-cannabis-based-asd-therapies/
Veterans Use Medical Marijuana to Treat Symptoms of Post-Traumatic Stress Disorder (PTSD) by Zach Reichard ShareTweet Veterans for Medical Cannabis Access (VMCA), is a Virginia-based non-profit service organization designed to assist veterans who wish to be able to use marijuana for medical purposes. They work towards safe access for veterans to medical marijuana without the fear of reprisal. Mike Krawitz, executive director of VCMA launched the “Allow United States Disabled Military Veterans Access to Medical Marijuana To Treat Their PTSD” petition last year. He said that he was concerned about military veterans risking losing their Veterans Affairs Department medical coverage if they are found to smoke pot or even discuss it with their doctors. The petition was on the White House website, and was signed by 8,258 people. The White House usually requires 25,000 signatures before it will respond to such petitions, so it was struck down. They claimed that marijuana is not considered a “benign drug,” and it doesn’t meet safe or effective medicine standards. “For many, cannabis not only treats PTSD… it’s considered a lifesaver,”Krawits told Military Times. Veterans and military troops transitioning back into civilian life are facing a number of disorders, and many are suffering severely. Post-traumatic stress disorder (PTSD) is an extremely severe anxiety disorder that many veterans develop after their psychological trauma they experienced while at war. It is a horrible disorder to endure and many veterans are currently being prescribed powerful addictive drugs to treat the symptoms. These drugs work for some, but others become addicted and the drugs are affecting their lives. The prevalence of substance abuse among veterans has increased substantially and some are even committing suicide. For this reason exactly, veterans are turning to cannabis more and more to deal with the crippling symptoms of PTSD, traumatic brain injuries, and chronic pain. In 2010 the U.S. Department of Veterans Affairs formally began to allow the use of medical marijuana by veterans treated at its medical facilities in states where it is legal. That means that veterans no longer have to worry about losing benefits if they test positive for marijuana in those states. Despite that fact, a number of veterans choose to self-medicate with the drug illegally rather than sign up for the medical-marijuana programs because of their distrust of the government. When Iraq veteran, Cory Woodstock, returned to his home in Arizona he was on 23 prescriptions, taking 57 pills a day. In 2009 he self-medicated with cannabis to prevent the voices he was hearing in his head and to ease the pain he was feeling throughout his entire body. However, once the drug showed up in a urine test for the U.S. Department of Veterans Affairs (VA), his doctor cut him off all prescriptions he needed for his pain. He quit smoking marijuana because he feared federal officials would strip him of his benefits. Woodstock tried other forms of treatment outside of the VA system to no avail. Nothing worked for him like marijuana: “It was an experiment, and it worked, I was able to sleep. I wasn’t so conscious about not being able to speak (well). I told the doctors I tried it and it helped. They said it voided my contract with the VA. I’m leery of the federal government. I’m not going to take the chance.” Woodstock said he wants to use marijuana to medicate, but he will not sign up for the medical marijuana state programs unless federal law enforcement changes its stance. This is a common position of veterans all across the country. In 2010, a national ABC News/Washington Post poll found that 81% of the country supports legalizing medical use, yet the government stubbornly denies access to the alternative medicine. Subsequently, in April of 2011 the FDA approved a clinical trial involving cannabis for treating PTSD. However, the trial is in current legal limbo because the Health and Human Services Department is making it difficult for the non-profit group to get the government-grown marijuana. With suicides outnumbering combat fatalities by a ratio of 25 to 1, and as much as 18% of Iraq veterans returning with PTSD, it would be negligent of the government to keep ignoring and delaying the issue
PTSD: Current Research • Preliminary, open-label, pilot study of add-on oral Δ9-
tTHC in chronic PTSD. Roitman P et. al. Hadassah Hebrew University Medical: 10 PTSD, on stable medication; THC 5 mg BID as add-on treatment.
• Mild adverse effects in 3 patients • Improvement in global symptom severity, sleep
quality, frequency of nightmares, and hyperarousal • THC was safe and well tolerated by patients
• DEA approves a controlled clinical trial. Funded by $2.156 million grant from Colorado DPH
• 76 veterans with TX-resistant PTSD in MD and AZ • Smoked cannabis with varying THC/CBD ratio • Naturalistic data on dosing, composition, side
effects, benefits
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Presentation Notes
The United States Drug Enforcement Administration (DEA) has given formal approval to a controlled clinical trial to study the effectiveness of whole-plant cannabis as a treatment for post-traumatic stress disorder (PTSD) in military veterans, the California-based non-profit Multidisciplinary Association for Psychedelic Studies (MAPS) announced last week. Post-traumatic stress disorder is an anxiety disorder that impacts an estimated eight million Americans each year, including military veterans returning from combat. To date, there are no pharmaceutical treatments specifically designed or approved to target symptoms of PTSD. “This study is a critical step in moving our botanical drug development program forward at the federal level to gather information on the dosing, risks, and benefits of smoked marijuana for PTSD symptoms.” – Amy Emerson, MAPS The study will be funded by a $2.156 million grant from the Colorado Department of Public Health and Environment (CDPHE) awarded to MAPS to sponsor the research. This marks the first time in history that any federal agency, including the DEA and the Food and Drug Administration (FDA), has approved a clinical trial with the intent of developing smokable, whole-plant marijuana into a prescription drug. “We have been working towards approval since we opened the Investigational New Drug Application (IND) with the FDA in 2010,” says Amy Emerson, Executive Director and Director of Clinical Research for the MAPS Public Benefit Corporation. “We are thrilled to see this study overcome the hurdles of approval so we can begin gathering the data. This study is a critical step in moving our botanical drug development program forward at the federal level to gather information on the dosing, risks, and benefits of smoked marijuana for PTSD symptoms.” According to a press release issued by MAPS on Thursday, the randomized, blinded, placebo-controlled study will test the safety and efficacy of botanical marijuana in 76 military veterans with treatment-resistant PTSD. The trial will gather safety and efficacy data on four potencies of smoked marijuana with varying ratios of tetrahydrocannabinol (THC) and cannabidiol (CBD). By exploring the effectiveness of a variety of marijuana strains, the study seeks to generate naturalistic data comparable to how many veterans in medical marijuana states currently use marijuana. Results will provide vital information on marijuana dosing, composition, side effects, and areas of benefit to clinicians and legislators considering marijuana as a treatment for PTSD. The study will be conducted at two locations in Arizona and Maryland, and will be overseen by Dr. Marcel Bonn-Miller, Ph.D., of the University of Pennsylvania’s Perelman School of Medicine. Half of the subjects participating in the study will be treated by Dr. Sue Sisley, a leading researcher on using marijuana to treat PTSD, in Phoenix, AZ. The other half of the subjects will be treated by Dr. Ryan Vandrey at Johns Hopkins University in Baltimore, MD. Blood analysis will be conducted at the University of Colorado, Boulder; and Dr. Paula Riggs, M.D., of the University of Colorado School of Medicine, will oversee the scientific integrity of the study. The approval of the study comes more than three years after Dr. Sisley first received approval from the US Department of Health and Human Services (HHS) to conduct clinical research on the effectiveness of medical marijuana in treating veterans suffering from PTSD. The study was expected to begin in 2014 at the University of Arizona, where Sisley worked as an assistant professor and researcher. The study soon stalled, however, when Sisley was fired from the University, allegedly retribution for her advocacy for medical marijuana research. To date, of the 24 states that have passed legislation to create comprehensive medical marijuana programs, only six — Arizona, Connecticut, Delaware, Maine, New Mexico, and Pennsylvania — explicitly allow PTSD as a qualifying condition for medical marijuana. Three other jurisdictions — California, the District of Columbia, and Massachusetts — allow physicians to recommend medical marijuana for conditions that aren’t specifically listed as qualifying conditions, including PTSD, if they feel the patient will benefit.
Traumatic Brain Injury • Effect of marijuana use on outcomes in traumatic brain
injury, Nguyen et al. UCLA, 2014 Oct. N=446, 3 year retrospective review. Overall mortality was 9.9%, mortality in THC group 2.4% A positive THC screen is associated with decreased mortality in adult TBI patients.
• MOA: Mouse model of closed head injury: Br J Pharmacol 2011 Aug
• Reduces glutamate, a toxic molecule • Decreases free radicals and TNF • Increases blood supply to the brain • Limits damage and edema • CB2 reduce white blood cell rolling and adhesion
reduce infarct size, improve motor function.
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Presentation Notes
The lack of cannabinoid-focused trials is likely due in part to the federal government’s long-standing position that cannabis is a “substance [with] no currently accepted medical use” and “a high potential for abuse” – a position that has long frustrated scientists who are forced to navigate significant bureaucratic obstacles to conduct high-quality rigorous studies. Nonetheless, despite the federal government’s position, there is some evidence that at least lends support to speculation that cannabis-derived treatments may be beneficial: "Effect of Marijuana Use on Outcomes in Traumatic Brain Injury" (UCLA Medical Center, 2014): In a three-year retrospective review of 446 separate cases of similarly injured patients, researchers found traumatic brain injury (TBI) patients who had a history of cannabis consumption possessed increased survival rates compared to non-consumers (97.6 percent survived surgery, versus 88.5% of those who didn’t consume cannabis). "[O]ur data suggest an important link between the presence of a positive THC screen and improved survival after TBI," the researchers concluded. "With continued research, more information will be uncovered regarding the therapeutic potential of THC, and further therapeutic interventions may be established." “Endocannabinoids and Traumatic Brain Injury” (Mechoulam, 2007): This Israeli study points to research that demonstrates: “…the [endocannabinoid] system…has the ability to [positively] affect the functional outcome after TBI by a variety of mechanisms.” “The Therapeutic Potential of the Cannabinoids in Neuroprotection” (Grundy RI, 2002): This review shows that in experimental models: “…various cannabinoids rescue dying neurons in experimental forms of acute neuronal injury, such as cerebral ischaemia and traumatic brain injury.”
• KannaLife Sciences, Inc. CTE and hepatic encephalopathy (HE) study. NIH license patent #6630507, “Cannabinoids as Antioxidants and Neuroprotectants”.
• reduction of oxidative stress • neuroprotectant by reducing swelling and
neurological impairment (Lopez-Rodriguez, et al., 2013) (Shohami, et al., 2011) (Castillo, et al., 2010) (Pazos, et al., 2013).
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Presentation Notes
The subject of the talk: chronic traumatic encephalopathy (CTE), a deterioration of the brain caused by repeated trauma to the head. Captured in a documentary by Frontline and a movie starring Will Smith called Concussion, the degenerative disease was initially thought to be a boxing injury only. But after studying the brain of former Pittsburgh Steeler’s center Mike Webster, Bennett Omalu penned a groundbreaking study revealing that football players—who endure years of head trauma—are at risk too. Among the disease’s side effects: memory loss, aggression, severe depression, anxiety, suicidal thoughts, and progressive dementia. In September, researchers from Boston University and the Department of Veterans Affairs released a report announcing that 96 percent of the brains of deceased pro-football players they studied have shown signs of CTE. Leonard Marshall, a former lineman for the New York Giants who opened the panel, says he’s suffered symptoms of CTE himself. KannaLife Science’s Cannabinoid-Based Treatment for CTE KannaLife Sciences, Inc., a plant-based pharmaceutical company, is actively developing a novel compound based on cannabinoids to treat CTE. The company is currently conducting research and development on sustainable hemp oil that is intended to act as a preventative and therapeutic modality for treating CTE and hepatic encephalopathy (HE). KannaLife holds an exclusive license with the National Institutes of Health (NIH) for the Commercialization of U.S. Patent #6630507, “Cannabinoids as Antioxidants and Neuroprotectants.” While research on cannabinoids’ effect specifically on CTE is lacking, studies have demonstrated that a major cannabinoid found in hemp, cannabidiol (CBD), reduces the oxidative stress that occurs in the brain following a traumatic brain injury. It has also serves as a neuroprotectant by reducing swelling and neurological impairment, therefore limiting brain damage and facilitating recovery (Lopez-Rodriguez, et al., 2013) (Shohami, et al., 2011) (Castillo, et al., 2010) (Pazos, et al., 2013).
Cancer • Animal models: cannabinoids inhibit tumor growth
• Human trials: not demonstrated
• MOA: Could inhibit one cancer and promote the growth of another:
• high doses inhibit growth • low doses proliferation of the same tumors
• May protect against head, neck, lung cancers
• May increase incidence of prostate, cervical, brain cancers
• Cancer pain: THC+CBD >effective THC alone • THC>25 mg/day is poorly tolerated • 2/3 studies: Sativex is effective, max dose 10
sprays/day (THC 27 mg+ CBD 25 mg/day)
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Presentation Notes
Cancer: pain Trial results suggest a combination of THC and CBD might be more effective than THC alone and that doses of THC higher than approximately 25 mg, even when divided over the course of a day, might be poorly tolerated by a substantial number of patients. The recently completed international trials of approximately 1:1 THC:CBD oromucosal spray (nabiximols, brand name Sativex) failed to meet their primary endpoints. However, a pre-specified pooled analysis of patients from U. S. Centers, from 2 of the 3 trials, showed better pain control with Sativex than with placebo. The maximum daily dosage allowed was 10 sprays per day, providing 27 mg THC and 25 mg CBD per day. Cancer: nausea and vomiting Several studies of plant-derived THC for chemotherapy-induced nausea and vomiting (CINV) from the late 1970s used 10 to 18 mg THC starting an hour or two before chemotherapy initiation, then repeating the dose every 2 to 4 hours for an additional 2 to 4 doses over 12 to 24 hours. Clinical trials of dronabinol, synthetic delta-9-THC, have used daily doses similar to the trials of plant-derived THC from the 1970s: 30 to 80 mg/day in divided doses. Not everyone can tolerate these doses, and the FDA recommends a lower dronabinol dose for CINV, stating most patients respond to 5 mg three or four times daily. Cancer: cachexia/wasting Some small early trials showed effectiveness with doses of plant-derived THC 10 to 15 mg three to four times daily on days of chemotherapy infusion. Later trials with dronabinol, mostly in cancer patients not receiving chemotherapy, are less encouraging. Using doses of 5.0 to 7.5 mg daily in divided doses there was either modest effectiveness compared to placebo or inferior effectiveness compared to standard anti-emetic drugs, and a substantial number of patients could not tolerate these doses. A large trial with cannabis extract treatment arms of relatively small doses of THC only (2.5 mg twice daily) or THC + CBD (2.5 mg THC/1.0 mg CBD twice daily) was stopped early for lack of effectiveness, yet dose reductions were necessary in a third of both groups.
Cancer: continued • Cancer nausea and vomiting: Plant THC, 1970s: 10-18 mg
THC 1-2 hrs before chemo, repeat Q2-4 hrs, 2-4 doses over 12-24 hrs.
• Clinical trials of dronabinol 30 to 80 mg/day in divided doses: intolerable side effects.
• FDA: Marinol 5 mg TID/QID
• Cancer cachexia/wasting: Small trials: effectiveness with plant-THC 10-15 mg TID/QID on days of chemo.
• Later trials with Marinol: less encouraging. • A large trial of THC only (2.5 mg BID) or THC + CBD
(2.5 mg THC/1.0 mg CBD BID): stopped early for lack of effectiveness dose reductions in 1/3 of both groups due to
intolerance.
Presenter
Presentation Notes
Cancer: pain Trial results suggest a combination of THC and CBD might be more effective than THC alone and that doses of THC higher than approximately 25 mg, even when divided over the course of a day, might be poorly tolerated by a substantial number of patients. The recently completed international trials of approximately 1:1 THC:CBD oromucosal spray (nabiximols, brand name Sativex) failed to meet their primary endpoints. However, a pre-specified pooled analysis of patients from U. S. Centers, from 2 of the 3 trials, showed better pain control with Sativex than with placebo. The maximum daily dosage allowed was 10 sprays per day, providing 27 mg THC and 25 mg CBD per day. Cancer: nausea and vomiting Several studies of plant-derived THC for chemotherapy-induced nausea and vomiting (CINV) from the late 1970s used 10 to 18 mg THC starting an hour or two before chemotherapy initiation, then repeating the dose every 2 to 4 hours for an additional 2 to 4 doses over 12 to 24 hours. Clinical trials of dronabinol, synthetic delta-9-THC, have used daily doses similar to the trials of plant-derived THC from the 1970s: 30 to 80 mg/day in divided doses. Not everyone can tolerate these doses, and the FDA recommends a lower dronabinol dose for CINV, stating most patients respond to 5 mg three or four times daily. Cancer: cachexia/wasting Some small early trials showed effectiveness with doses of plant-derived THC 10 to 15 mg three to four times daily on days of chemotherapy infusion. Later trials with dronabinol, mostly in cancer patients not receiving chemotherapy, are less encouraging. Using doses of 5.0 to 7.5 mg daily in divided doses there was either modest effectiveness compared to placebo or inferior effectiveness compared to standard anti-emetic drugs, and a substantial number of patients could not tolerate these doses. A large trial with cannabis extract treatment arms of relatively small doses of THC only (2.5 mg twice daily) or THC + CBD (2.5 mg THC/1.0 mg CBD twice daily) was stopped early for lack of effectiveness, yet dose reductions were necessary in a third of both groups.
Pain: continued • The most common symptom for which patients report
using MC • Adjunct TX for opioid medications • Reduce the amount of opioid • Restore opioid pain relief, reduce opioid tolerance,
reduce opioid withdrawal severity • Reduce GI bleed from nonsteroidal
• Dosage: UCASD human study, Sativex study: • Small dose: no effect • Medium dose: reduced pain significantly • High dose: increased pain significantly
• Method: oral for chronic pain, Inhaled: titration
Glaucoma • CBD: not effective, may increase IOP • Some studies: THC 5 mg may reduce IOP for 4-
5 hrs (not consistent) • Large doses (20-25 mg) reduce IOP for 10 hrs,
but with intolerable side effects
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Presentation Notes
CBD does not appear to be effective at lowering intraocular pressure (IOP) and might even increase it. There is some evidence that even relatively low (5 mg) single doses of THC significantly reduces IOP for 4 to 5 hours before it returns to baseline, but this isn’t a consistent finding across studies. Larger single doses (20 and 25 mg) appear to reduce IOP longer (10 hours), but with a high occurrence of intolerable side effects.
Each of the studies identified used dronabinol and assessed effect on appetite and weight. Most used 5.0 to 7.5 mg daily in 2 or 3 divided doses, consistent with FDA label recommendations. Though most patients tolerated this dose well, a substantial minority could only tolerate 2.5 mg daily. Results from three trials that enrolled current marijuana users suggest current marijuana users can tolerate higher doses, in the range of 20 to 40 mg daily in divided doses. While the side effects of HIV and AIDS treatment can impinge on life quality, studies have shown that medical marijuana can help make the adverse effects more manageable. HIV positive patients consuming medical marijuana have reported significant improvements in appetite, muscle pain levels, nausea, anxiety, depression and skin tingling (Woodridge, et al., 2005). Studies have found that daily and chronic neuropathic pain related to HIV can be significantly lowered by regular cannabis consumption (Ellis, et al., 2008) (Abrams, et al., 2007). Medical marijuana also boosts appetite and daily functioning, helping to combat weight loss and muscle breakdown (Haney, Rabkin, Gunderson & Foltin, 2005). Research also suggests that consuming medical marijuana is safe for patients with HIV/AIDS. One study found no significant association with cannabis use and the CD4 T-cell count of patients co-infected with HIV and HCV, which means medical marijuana had no adverse effects on the immune system (Marcellin, et al., 2016). Another study found that patients with an HIV/HCV co-infection that smoked marijuana were at no greater risk of liver fibrosis (Brunet, et al., 2013). While research surrounding marijuana’s potential treatment effects on the HIV virus itself, a recent study discovered that marijuana-like compounds blocked the spread of HIV virus during the infection’s late stages (Costantino, et al., 2012). Results from an animal trial also suggest that marijuana might be able to stop the spread of HIV. Monkeys that were infected with an animal form of the virus and administered with THC for 17 months saw a decrease in damage to the immune tissue of the stomach (Molina, et al., 2014).
Multiple Sclerosis and Movement Disorders • Numerous trials: THC 20-25 mg/day in divided doses.
• Slow titration over weeks to reduce AE
• THC in high doses works better for spasticity (better tolerated with THC/CBD 1:1 ratio.
• Effective in 50% patients
• U of CA Center for Medical Cannabis Research (CMCR): 30 MS patients, placebo-controlled study, significant reduction in spasticity, pain reduced by 50%
Results of numerous trials focusing on spasticity and muscle spasm have been published, mostly with multiple sclerosis patients, but also some with spinal cord injury patients. Whether in combination with CBD in various ratios or as a single agent (dronabinol), THC has been used in average dosages of 20 to 25 mg/day in divided doses. Dosages are usually started fairly low and then titrated up to achieve a balance between symptom reduction and appearance of side effects. From the trial experience, it appears that doing this titration over weeks, rather than over days, helps to reduce incidence and severity of side effects. There is some indication that THC is more effective in reducing spasticity and spasm at higher doses and that higher doses are better tolerated when given in conjunction with CBD in a THC:CBD ratio of 1:1 (versus 2:1 or 3:1 or dronabinol). But some patients cannot tolerate even quite low doses of THC. Treatment appears to be effective in only a subset of patients, perhaps around half, and whether or not treatment will be effective can generally
• Five (7%): aggravation of seizures • Improvement in behavior and alertness, language,
communication, motor skills and sleep • Adverse reactions: somnolence, fatigue, GI
disturbances and irritability
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Presentation Notes
Methods A retrospective study describing the effect of cannabidiol (CBD)-enriched medical cannabis on children with epilepsy. The cohort included 74 patients (age range 1–18 years) with intractable epilepsy resistant to >7 antiepileptic drugs. Forty-nine (66%) also failed a ketogenic diet, vagal nerve stimulator implantation, or both. They all started medical cannabis oil treatment between 2–11/2014 and were treated for at least 3 months (average 6 months). The selected formula contained CBD and tetrahydrocannabinol at a ratio of 20:1 dissolved in olive oil. The CBD dose ranged from 1 to 20 mg/kg/d. Seizure frequency was assessed by parental report during clinical visits. Results CBD treatment yielded a significant positive effect on seizure load. Most of the children (66/74, 89%) reported reduction in seizure frequency: 13 (18%) reported 75–100% reduction, 25 (34%) reported 50–75% reduction, 9 (12%) reported 25–50% reduction, and 19 (26%) reported <25% reduction. Five (7%) patients reported aggravation of seizures which led to CBD withdrawal. In addition, we observed improvement in behavior and alertness, language, communication, motor skills and sleep. Adverse reactions included somnolence, fatigue, gastrointestinal disturbances and irritability leading to withdrawal of cannabis use in 5 patients. Conclusions The results of this multicenter study on CBD treatment for intractable epilepsy in a population of children and adolescents are highly promising. Further prospective, well-designed clinical trials using enriched CBD medical cannabis are warranted.
Reported trials that appear to have enrolled mostly adults each used 200 or 300 mg CBD daily with two of the three suggesting evidence of effectiveness at reducing seizure severity. A recent survey of parents of children with epilepsy treated with CBD extract indicates a very wide range of daily dose, but the results are hard to interpret because of lack of standardization of the CBD preparations used. Recent studies mostly or entirely focusing on children have used 99% CBD extract, starting at a dose of 2 to 5 mg/kg/day, titrating up slowly to a goal of 25 to 50 mg/kg/day. https://www.gwpharm.com/products-pipeline/ Lennox-Gastaut syndrome, Tuberous Sclerosis Complex, and Infantile Spasms Epilepsy GW’s pipeline in the field of epilepsy currently includes two product candidates: Epidiolex® (CBD) and GWP42006 (CBDV). Epidiolex® (cannabidiol) Epidiolex is a liquid formulation of pure plant-derived Cannabidiol (CBD) as a treatment for various orphan pediatric epilepsy syndromes. GW has been conducting pre-clinical research of CBD in epilepsy since 2007. This research has shown that CBD has significant anti-epileptiform and anticonvulsant activity using a variety of in vitro and in vivo models and that it has the ability to treat seizures in acute animal models of epilepsy with significantly fewer side effects than existing AEDs. GW’s strategy for the development of Epidiolex within the field of childhood-onset epilepsy is to initially concentrate formal development efforts on four orphan indications: Dravet syndrome, LGS, TSC, and IS, each of which are severe infantile-onset, drug-resistant epilepsy syndromes. GW expects to further expand the potential market opportunity of Epidiolex by targeting additional orphan seizure disorders. GWP42006 In addition to Epidiolex, our epilepsy product candidates also include GWP42006, which features CBDV as the primary cannabinoid. CBDV is distinct in chemical structure to CBD and has also shown anti-epileptic properties across a range of in vitro and in vivo models of epilepsy. In a paper published in the September 2012 issue of The British Journal of Pharmacology, GWP42006 strongly suppressed seizures in six different experimental models commonly used in epilepsy treatment. GWP42006 was also found to provide additional efficacy signals when combined with drugs currently used to control epilepsy. Genetic biomarkers for response have been identified. We have completed a Phase 1 trial of GWP42006 in 66 healthy subjects. In this trial, GWP42006 was well tolerated even at the highest tested dose. There were no serious or severe adverse events reported, nor any withdrawals due to adverse events. We have commenced a Phase 2 trial of GWP42006 in 130 patients with epilepsy and expect results in 2017. As part of our agreement with the government of New South Wales in Australia, we expect an additional trial of GWP42006 to commence in 2016 in children with treatment-resistant epilepsy. We believe that GWP42006 has the potential for development in the field of pediatric epilepsy as well as the broader epilepsy market. Autism Spectrum Disorders Many of the pediatric intractable epilepsy conditions within the Epidiolex Expanded Access Program share considerable overlap with Autism Spectrum Disorders (ASD). Early clinical observations from treating physicians suggest a potential role for cannabinoids in addressing certain problems associated with ASD; they may be able to treat deficits in cognition, behavior and communication. GW is working with investigators to gain clinical experience in the use of different cannabinoids for the treatment of Autism Spectrum Disorders and we have a number of ongoing initiatives to evaluate a range of cannabinoids in pre-clinical models of ASD, including an assessment of the effect of cannabinoids on cognitive and behavioral function in animal models of conditions characterized as being on the 'autism spectrum'. These animal models include both genetically determined abnormalities of neurobehaviour, and chemically-induced models, and include Rett syndrome and Fragile X among others. Glioma We are evaluating a product containing a proprietary CBD:THC combination in the treatment of recurrent glioblastoma multiforme, or GBM, a particularly aggressive brain tumor which is considered a rare disease by the FDA and the European Medicines Agency. A recent study carried out in collaboration with us by specialists at St George’s, University of London, was the first to show an effect on brain tumors when combining cannabinoids with irradiation. This research, published in Molecular Cancer Therapeutics, showed that tumor growth in mouse brain was significantly slowed when this combination of THC and CBD was used with irradiation and tumor inhibition was higher than observed with irradiation alone. In 2014, we commenced an early proof of concept Phase 1b/2a clinical trial in 20 patients with recurrent GBM evaluating GWP42002:GWP42003 (THC/CBD) in combination with temozolomide, the current standard of care. This study is a two part study with an open-label phase to assess safety and tolerability followed by a double blind, randomized, placebo-controlled phase with patients randomized to receive active or placebo. The first phase, an open-label safety evaluation of GWP42002:GWP42003 comprising two cohorts of three patients each completing two cycles (months) of treatment is now complete. Safety data from these initial patient cohorts has been assessed by the independent safety monitoring board and their approval was given to proceed into a Phase 2a placebo-controlled phase. We have now completed recruitment of the 20 patient placebo-controlled 2a phase of the trial. Neonatal Hypoxic-Ischemic Encephalopathy (NHIE) NHIE is acute or sub-acute brain injury due to asphyxia caused during birth resulting from deprivation of oxygen during birth (hypoxia) as a result of a sentinel event such as ruptured placenta, parental shock and even increased heart rate. Hypoxic damage can occur to most of the infant’s organs, but brain damage is the most serious and least likely to heal, resulting in encephalopathy. This can later manifest itself as either mental retardation (including developmental delay and/or intellectual disability) or physical disabilities such as spasticity, blindness and deafness. The exact timing and underlying causes of these outcomes remains unknown but it is widely recognized that interventions need to be administered within six hours of hypoxic insult. We are developing an intravenous CBD formulation in the treatment of NHIE. In April 2015, we received Orphan Drug Designation from the FDA for CBD for the treatment of NHIE in July 2015 and we received Orphan Drug Designation from the EMA for CBD for the treatment of perinatal asphyxia, an alternative term for the same condition. In addition, in July 2015 we received Fast Track Designation from the FDA. Schizophrenia Schizophrenia is a chronic disease that manifests through disturbances of perception, thought, cognition, emotion, motivation and motor activity. Over a lifetime, about 1% of the population will develop schizophrenia. Our product, GWP42003, has shown notable anti-psychotic effects in accepted pre-clinical models of schizophrenia and importantly has also demonstrated the ability to reduce the characteristic movement disorders induced by currently available anti-psychotic agents. In September 2015, we announced top line results from an exploratory Phase 2a placebo-controlled clinical trial of CBD in 88 patients with schizophrenia who had previously failed to respond adequately to first line anti-psychotic medications. We believe that the signals demonstrated in this trial, together with the safety profile, provide us with the prospect of new and distinct cannabinoid neuropsychiatric product pipeline opportunity, as the mechanism of CBD does not appear to rely on the dopamine D2 receptor augmentation of standard antipsychotics. We are now analyzing the data to fully understand the appropriate next steps regarding product development in schizophrenia with future research likely focused on pediatric orphan neuropsychiatric indications. Cerebral Palsy in Children GW is currently conducting a study to assess the efficacy, safety and tolerability of Sativex as an adjunctive treatment to existing anti-spasticity medications in children aged 8 to 18 with spasticity due to cerebral palsy or traumatic central nervous system injury who have not responded adequately to existing anti-spasticity medications. This study is a randomized, double-blind, placebo-controlled study followed by a 24-week open label extension phase and is expected to enroll approximately 70 patients. research-trials/therapeutic-areas During the treatment period, patients taking Epidiolex 20mg/kg/day achieved a median reduction in monthly drop seizures of 42 percent compared with a reduction of 17 percent in patients taking placebo (p=0.0047), and patients taking Epidiolex 10mg/kg/day achieved a median reduction in monthly drop seizures of 37 percent compared with a reduction of 17 percent in patients taking placebo (p=0.0016). https://globenewswire.com/news-release/2016/09/26/874464/0/en/GW-Pharmaceuticals-Announces-Second-Positive-Phase-3-Pivotal-Trial-for-Epidiolex-cannabidiol-in-the-Treatment-of-Lennox-Gastaut-Syndrome.html
• UDAS: (-) for cannabis, frequent change in formulation, laced with drugs, rat poison, embalming fluids
Presenter
Presentation Notes
Recent outbreaks of synthetic cannabinoids-related emergency department visits across the country has been in the news lately. Between April 1 and 31 May, 2015, Mississippi reported 1243 emergency department visits due to adverse events from synthetic cannabinoids, with 10% requiring intensive care unit admission, 11% non-ICU admission and 17 potentially related deaths. he United States experienced at 229% increase in poisoning attributable to cannabinoids from January to May 2015 when compared to the same time period in 2014. Although these illegal substance are commonly referred to as synthetic cannabinoids, cannabinoids receptor agonists, spice, they should not be confused with cannabis. Illegal synthetic cannabinoids are not cannabis but rather at collection of numerous laboratory chemicals that interact with cannabinoid receptors in the brain to mimic marijuana to induce marijuana-like high. Synthetic cannabinoids are more potent than cannabis. Chemical components bind more strongly to the cannabinoid receptor in the brain that cannabis does not. Symptoms may resolve spontaneously without intervention and vary, including mild to moderate intoxication-like symptoms, nausea emesis, weakness, tachycardia, hypertension, and agitation. Several news reports have described users in states of excited delirium, significantly agitated, tearing off their clothes, and sweating profusely. Severe symptoms include significant cardiac arrhythmias, myocardial infarction, psychosis, respiratory depression, flaccid paralysis, hyperthermia, rhabdomyolysis, seizures, and even death. Intoxication management usually centers on airway, breathing, circulation, followed by supportive care. Fluid resuscitation may be needed, as well as electrolyte correction. Benzodiazepines are usually first line treatment for anxiety and agitation, physical restraints may be necessary. Significant psychosis with behavioral disturbances can occur, which may not be calmed with typical methods, in these instances, antipsychotics may be helpful. In some cases the atypical antipsychotics tend to assist more than the benzodiazepines. However, caution should be used with antipsychotics and other medications that can decrease seizure threshold as there have been reports of synthetic cannabinoids causing seizures. Synthetic cannabinoids are scheduled one, making his products illegal to sell, buy or possess. The manufacturers change the chemical formulations to evade the law enforcement. The full extent of their psychological and toxicological effect is unknown at this time. Because synthetic cannabinoids are not cannabis, they will not show up as cannabis on a typical urine drug screen. Current probation testing will detect some specific compounds, but with rapidly changing components, even confirmation detection is unlikely. The user does not really know what they are consuming because the chemicals are rapidly changing: amount of drug is unknown. Many of these products are laced with substances ranging from simple flavors to more danger substances such as other drugs, rat poison in embalming fluids.
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• Dronabinol and marijuana in HIV-positive marijuana smokers. Calorie intake, mood, and sleep. (http://www.ncbi.nlm.nih.gov/pubmed/17589370)
• Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial. (http://www.ncbi.nlm.nih.gov/pubmed/12965981)
• Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066045/)
• Preliminary, open-label, pilot study of add-on oral Δ9-tetrahydrocannabinol in chronic post-traumatic stress disorder. Roitman P1, Mechoulam R, Cooper-Kazaz R, Shalev A.
References • CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience
Michal Tzadoka, 1, , , Shimrit Uliel-Sibonib, 1, Ilan Linderc, Uri Kramerb, Orna Epsteind, Shay Menascub, Andrea Nissenkorna, Omer Bar Yosefa, Eli Hymand, Dorit Granote, Michael Dorf, Tali Lerman-Sagiec, Bruria Ben-Zeeva
• We need to reschedule cannabis. A sane solution to an irrational standoff. Bostwick JM.
